The proposed research involves investigations of the genetic regulation of aflatoxin B1 (AFB1) metabolism via activation and deactivation pathways; the effects of environmental factors, i.e., polycyclic aromatic hydrocarbons (PAH's) that determine the genetic regulation of AFB1 metabolism in mice, on the metabolism of AFB1 by humans; and the role of the genetics of AFB1 metabolism in carcinogenesis and toxicity. Compounds to be studied will include AFB1 and inducers that cause induction or the repression of the specific pathways of AFB1 metabolism. The objectives of these studies are: (a) to understand the genetic regulation of AFB1 metabolism via various pathways, including activation and detoxification; (b) develop genetic models for studies on aflatoxin carcinogenesis and toxicity; (c) define the role of the genetic regulation of AFB1 metabolism via various pathways in the determination of susceptibility to aflatoxin B1; and (d) study the effect of smoking on the metabolism of AFB1 by placental tissue obtained post-delivery. Much of the proposed work will be performed (a) in vitro with labeled AFB1, DNA, hepatic microsomes and other subcellular fractions isolated from rats, and human placental tissue, and (b) in vivo with different strains of rats and mice for the purpose of investigaing the correlation between in vitro metabolism and in vivo metabolic activation in an effort to assess the role of the genetics of AFB1 metabolism in toxicity and carcinogenesis. Particular methods to be used include: radiochemical techniques, thin layer chromatography, spectroscopy, ultracentrifugation techniques, HPLC and other biochemical and enzymological methods.